BASIS OF GENETIC SUSCEPTIBILITY OF MURINE EAE

The purpose of this proposal is to test the hypothesis that mouse strains that are genetically susceptible to the induction of experimental allergic encephalomyelitis (EAE) i.e. SJL/J) have cellular and/or environmental defects that allow for the generation of abnormal T cells which are not present in strains that are genetically EAE- resistant (i.e. B10.S). In order to do, the following questions will be addressed: 1) Is the susceptibility of SJL/J mice to EAE induction due to an intrinsic defect at the prothymocyte level and/or the microenvironment in which these cells mature? 2) What is the basis of the resistance of B10.S mice to EAE induction? We will use a quantitative radiation bone marrow chimera system between EAE-susceptible SJL/J (H-2s; thy 1.2) and EAE-resistant B10.S Thy 1.1 (H-2s; Thy 1.1) mice to determine whether SJL/J prothymocytes can transfer the predisposition for the development of EAE to naive B10.S Thy 1.1 recipients and/or whether the SJL/J environment can confer such a predisposition upon B10.S Thy 1.1 prothymocytes maturing under its influence. In addition, we will use in vitro culture, cloning, in situ immunohistochemistry, in vitro priming and adoptive transfer of cultured T cells to naive unirradiated recipients to investigate the basis for the apparent cellular resistance of B10.S/B10.S Thy 1.1 mice to the development of EAE. These strategies should be useful in further elucidating the mechanisms involved in the pathogenesis of EAE, and possibly by extension, multiple sclerosis.